Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells.

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.

Evaluating the effects of a global pandemic on the operation of an investigational drug service.

PURPOSE: This study is an analysis of the changes to workload and operations of UNC Health's investigational drug service (IDS) brought about by the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Workload statistics were collected and analyzed for trend changes to illustrate operational changes necessitated by the COVID-19 pandemic within the IDS pharmacy at UNC Health. RESULTS: Multiple workload metrics declined at the beginning of the COVID-19 pandemic, followed by an increase in the metrics for many categories as the pandemic continued. Notably, monthly inventory added initially decreased by 37.5%, later leveling off but showing increased variability. Fills dispensed and monitoring visits both decreased by 34.5% from the first quarter (Q1) to Q2 of 2020. Both metrics returned to or slightly exceeded prepandemic levels by the end of the study period in March 2021. Patient enrollment decreased 76% from February to May 2020 before dramatically increasing in Q3 of 2020 and Q1 of 2021 with the initiation of COVID-19 vaccine studies. The average time to study startup increased for trials not related to COVID-19 and decreased for COVID-19-related trials. There has been no major impact on the number of open protocols throughout the course of the pandemic. CONCLUSION: Despite initial decreases in workload following the start of the COVID-19 pandemic, IDS operations returned to and, in some cases, exceeded prepandemic levels.

Investigational antiviral drugs for the treatment of COVID-19 patients.

In the current pandemic of coronavirus disease 2019 (COVID-19), antiviral drugs are at the center of attention because of their critical role against severe acute respiratory disease syndrome coronavirus 2 (SARS-CoV-2). In addition to designing new antivirals against SARS-COV-2, a drug repurposing strategy is a practical approach for treating COVID-19. A brief insight about antivirals would help clinicians to choose the best medication for the treatment of COVID-19. In this review, we discuss both novel and repurposed investigational antivirals, focusing on in vitro, in vivo, and clinical trial studies.

Oncologists' reflections on patient rights and access to compassionate use drugs: A qualitative interview study from an academic cancer center.

The U.S. Food and Drug Administration (FDA) allows patients with serious illnesses to access investigational drugs for "compassionate use" outside of clinical trials through expanded access (EA) Programs. The federal Right-to-Try Act created an additional pathway for non-trial access to experimental drugs without institutional review board or FDA approval. This removal of oversight amplifies the responsibility of physicians, but little is known about the role of practicing physicians in non-trial access to investigational drugs. We undertook semi-structured interviews to capture the experiences and opinions of 21 oncologists all with previous EA experience at a major cancer center. We found five main themes. Participants with greater EA experience reported less difficulty accessing drugs through the myriad of administrative processes and drug company reluctance to provide investigational products while newcomers reported administrative hurdles. Oncologists outlined several rationales patients offered when seeking investigational drugs, including those with stronger health literacy and a good scientific rationale versus others who remained skeptical of conventional medicine. Participants reported that most patients had realistic expectations while some had unrealistic optimism. Given the diverse reasons patients sought investigational drugs, four factors-scientific rationale, risk-benefit ratio, functional status of the patient, and patient motivation-influenced oncologists' decisions to request compassionate use drugs. Physicians struggled with a "right-to-try" framing of patient access to experimental drugs, noting instead their own responsibility to protect patients' best interest in the uncertain and risky process of off-protocol access. This study highlights the willingness of oncologists at a major cancer center to pursue non-trial access to experimental treatments for patients while also shedding light on the factors they use when considering such treatment. Our data reveal discrepancies between physicians' sense of patients' expectations and their own internal sense of professional obligation to shepherd a safe process for patients at a vulnerable point in their care.

When innovation outpaces regulations: The legal challenges for direct-to-patient supply of investigational medicinal products.

AIMS: We profile the lack of specific regulation for direct-to-patient postal supply (DTP) of clinical trial medications (investigational medicinal products, IMPs) calling for increased efficiency of patient-centred multi-country remote clinical trials. METHODS: Questionnaires emailed to 28 European Economic Area (EEA) Medical Product Licensing Authorities (MPLAs) and Swissmedic MPLA were analysed in 2019/2020. The questionnaire asked whether DTP of IMPs was legal, followed by comparative legal analysis profiling relevant national civil and criminal liability provisions in 30 European jurisdictions (including The Netherlands), finally summarising accessible COVID-19-related guidance in searches of 30 official MPLA websites in January 2021. RESULTS: Twenty MPLAs responded. Twelve consented to response publication in 2021. DTP was not widely authorised, though different phrases were used to explain this. Our legal review of national laws in 29 EEA jurisdictions and Switzerland did not identify any specific sanctions for DTP of IMPs; however, we identified potential national civil and criminal liability provisions. Switzerland provides legal clarity where DTP of IMPs is conditionally legal. MPLA webpage searches for COVID-19 guidance noted conditional acceptance by 19 MPLAs. CONCLUSIONS: Specific national legislation authorising DTP of IMPs, defining IMP categories, and conditions permitting the postage and delivery by courier in an EEA-wide clinical trial, would support innovative patient-centred research for multi-country remote clinical trials. Despite it appearing more acceptable to do this between EU Member States, provided each EU MPLA and ethics board authorises it, temporary Covid-19 restrictions in national Good Clinical Practice (GCP) guidance discourages innovative research into the safety and effectiveness of clinical trial medications.

Participation in ENSEMBLE phase III multicenter clinical trial of Ad26.CoV2.S, a COVID-19 vaccine: An investigational drug services perspective.

WHAT IS KNOWN AND OBJECTIVE: Since WHO declared the pandemic of COVID-19, vaccines have been developed to fight against this infectious disease. Coordination and participation of investigational drug services to facilitate a phase III COVID-19 vaccination clinical trial are described and discussed, with novel interventions coordinating the dispensing processes in the trailer settings. COMMENT: Once the study has reached phase III, the large number of participants and fast enrolment would contribute to the vaccine development. WHAT IS NEW AND CONCLUSION: The investigational drug service (IDS) performed responsibilities in clinical and trailer units, and minimized workflow disturbances to maximize validity during the dispensing process. The advantages of mobile units and trailers increase flexibility of participants, broaden service area and improve feasibility, especially in minority and underserved communities. The UCM IDS team performs responsibilities in both clinical and mobile unit settings, the IDS team is able to facilitate and expand the enrolment to the minority population in underserved communities.

[Real-life data and Covid-19: The third avenue of reseach]. / Données de vie réelle et Covid-19 : la troisième voie.

The analysis of real-life data from hospital information systems could make possible to decide on the efficacy and safety of Covid-19 treatments by avoiding the pitfalls of preliminary studies and randomized clinical trials. The different drugs tested in current clinical trials are already widely prescribed to patients by doctors in hospitals, and can therefore be immediately analysed according to validated methodological standards.

Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs.

Coronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

COVID-19 treatment options: a difficult journey between failed attempts and experimental drugs.

Since its outbreak in China in December 2019 a novel Coronavirus, named SARS-CoV-2, has spread worldwide causing many cases of severe pneumonia, referred to as COVID-19 disease, leading the World Health Organization to declare a pandemic emergency in March 2020. Up to now, no specific therapy against COVID-19 disease exists. This paper aims to review COVID-19 treatment options currently under investigation. We divided the studied drugs into three categories (antiviral, immunomodulatory and other drugs). For each molecule, we discussed the putative mechanisms by which the drug may act against SARS-CoV-2 or may affect COVID-19 pathogenesis and the main clinical studies performed so far. The published clinical studies suffer from methodological limitations due to the emergency setting in which they have been conducted. Nevertheless, it seems that the timing of administration of the diverse categories of drugs is crucial in determining clinical efficacy. Antiviral drugs, in particular Remdesivir, should be administered soon after symptoms onset, in the viraemic phase of the disease; whereas, immunomodulatory agents, such as tocilizumab, anakinra and steroids, may have better results if administered in pneumonia/hyperinflammatory phases. Low-molecular-weight heparin may also have a role when facing COVID-19-related coagulopathy. Up to now, treatment choices have been inferred from the experience with other coronaviruses or viral infection outbreaks. Hopefully, in the near future, new treatment strategies will be available thanks to increased knowledge on SARS-CoV2 virus and COVID-19 pathogenesis. In the meanwhile, further well-designed clinical trials are urgently needed to establish a standard of care in COVID-19 disease.

Clinical research in hospital pharmacy during the fight against COVID-19.

The health crisis resulting from the rapid spread of SARS-CoV-2 worlwide, added to the low evidence of currently used treatments has led to the development of a large number of clinical trials (CT) and observational studies. Likewise,  important measures have been adopted in healthcare and research centers  aimed at halting the pandemic as soon as possible. The objective of this study is  to gather the main aspects of the clinical research studies undertaken by the  Departments of Hospital Pharmacy (DHP) of Spain during the COVID-19 crisis. The decision of the Spanish Society of Hospital Pharmacy (SEFH) to sponsor CTs made it possible that 13% of DHP had been led at least one CT.  The Spanish Agency for Medicines and Medical Devices (AEMPS), in coordination  with Institutional Review Boards, has adopted a fast-track review procedure to  accelerate authorizations for CTs related to the treatment or prevention of  COVID-19. There have also been numerous public and private calls for financing  research projects aimed at contributing to the fight against this virus. Despite  the pandemic, actions have been taken to continue ongoing CTs and studies  while the safety and well-being of patients are guaranteed. More specifically, the AEMPS and the European Medicines Agency (EMA) have issued guidelines that  incorporate changes to CT protocols that will have to be applied until the  pandemic is over. In this health emergency, the scientific community has found  itself in a race against time to generate evidence. It is at this moment that  hospital pharmacists emerge as key players in clinical research and are  contributing to a rational, effective and safe healthcare decision-making.

La presente crisis sanitaria derivada de la rápida expansión del virus SARS-CoV- 2 a nivel mundial, así como la falta de evidencia de los tratamientos empleados  actualmente, ha provocado la aparición de un gran número de ensayos clínicos y estudios observacionales. Del mismo modo, ha ocasionado la puesta en marcha  de importantes medidas en el entorno sanitario e investigador con el fin de  conseguir detener la evolución de la pandemia lo antes posible. El objetivo del  actual trabajo es recopilar aspectos fundamentales relacionados con la  investigación clínica desarrollada por los servicios de farmacia hospitalaria  durante la crisis provocada por la COVID-19. La iniciativa de la Sociedad  Española de Farmacia Hospitalaria de actuar como promotor de ensayos clínicos  ha posibilitado que el 13% de estos servicios de farmacia hospitalaria haya  podido liderar uno. En este sentido, la Agencia Española de Medicamentos y  Productos Sanitarios, junto con los Comités de Ética de Investigación, ha  acelerado los procedimientos de autorización de nuevos ensayos clínicos  destinados a tratar o prevenir la COVID-19. Asimismo, han sido numerosas las  convocatorias públicas y privadas destinadas a la financiación de proyectos de  diversa índole con el fin de contribuir a la lucha contra este virus. A pesar de la  irrupción de la pandemia, también han surgido acciones destinadas a mantener  las actividades de los ensayos clínicos y estudios puestos previamente en  marcha, garantizando la seguridad y bienestar del paciente. Concretamente, la  Agencia Española de Medicamentos y Productos Sanitarios y la Agencia Europea  de Medicamentos han publicado guías que incluyen cambios en los protocolos de los ensayos clínicos que deben mantenerse mientras dure la pandemia. La  emergencia sanitaria actual ha obligado a la comunidad científica a la generación de evidencia a contrarreloj. Por ello, en este momento en el que se requiere del  mayor rigor posible, el farmacéutico de hospital debe alzarse como una figura  clave en la investigación en salud, contribuyendo a que las decisiones sanitarias  sean racionales, eficientes y seguras.

Practice considerations on the use of investigational anti-COVID-19 medications: Dosage, administration and monitoring.

WHAT IS KNOWN AND OBJECTIVE: Understanding investigational medications is important. Many older drugs are being investigated for repurposing against COVID-19. We comment on various drugs currently undergoing such trials to optimize their safe use. COMMENT: We describe medications used during early COVID-19 outbreaks in South Korea, focusing on practice aspects including the method of drug administration, drug formulation, patient-monitoring for adverse reactions and drug interactions informed by our experience during the 2015 outbreak of Middle East respiratory syndrome (MERS). We comment on hydroxychloroquine, chloroquine, lopinavir/ritonavir with zinc supplement, remdesivir, tocilizumab, ciclesonide, niclosamide and high-dose intravenous immunoglobulin (IVIG). WHAT IS NEW AND CONCLUSION: Effective therapies are urgently needed to manage COVID-19, and existing drugs such as antivirals and antimalarials are under investigation for repurposing to meet this need. This process requires up-to-date drug information to ensure optimum use, particularly safety and efficacy profiles of the medications, until convincing evidence is reported.

Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.